Thromboxane ligands without blood clotting side effects

ABSTRACT

A method of treating ocular hypotension, hypertension, hemorrhage, myocardial ischemia, angina pectoris, coronary contraction, cerebrovascular contraction after subarachnoidal hemorrhage, cerebral hemorrhage and asthma which comprises administering to a mammal suffering therefrom a therapeutically effective amount of a thromboxane ligand which is a compound formula I,  
                 
 
wherein Y is (CH 2 ) x ; Z is selected from the group consisting of
 
 
                 
 
O, OCH 2 , O—C—O and (CR 2 ) x , x is an integer of 1 or 2; n is 0 or 1; R 2  is hydrogen or an alkyl radical of from 1 to 4 carbons; A is an alkylene or alkenylene radical having from two to seven carbon atoms, which radical may be substituted with one or more hydroxy, oxo, alkyloxy or alkylcarboxy groups or said alkylene or alkenylene may have one or more enchained oxa or imino radicals; B is a methyl radical or a cycloalkyl radical having from three to seven carbon atoms, or an aryl radical, selected from the group consisting of hydrocarbyl aryl and heteroaryl radicals wherein the heteroatom is selected from the group consisting of nitrogen, oxygen and sulfur atoms, or substituted derivatives of said methyl, cycloalkyl or aryl radicals wherein said substituent is selected from the group consisting of halo, nitro, amino, thiol, hydroxy, alkyloxy and alkylcarboxy; and X is selected from the group consisting of nitro, cyano, —COOR, —CH 2 OR 1 , —C(O)N(R 1 ) 2 , —CH 2 N(R 1 ) 2 —CH═N—OH and —CH 2 SR 1  radicals wherein R is a C 1  to C 10  alkyl, phenyl or benzyl and R 1  is R or hydrogen; or a pharmaceutically acceptable salt thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation of U.S. patent applicationSer. No. 10/213,190, filed on Aug. 5, 2002, which patent application isa continuation of U.S. patent application Ser. No. 09/899,713 filed onJul. 5, 2001, now U.S. Pat. No. 6,462,077 which is a continuation inpart of U.S. patent application Ser. No. 09/334,356 filed on Jun. 16,1999, now abandoned, which is a continuation of U.S. patent applicationSer. No. 09/038,068 filed on Mar. 11, 1998, now abandoned, which is acontinuation of U.S. patent application Ser. No. 08/832,431 filed onApr. 2, 1997, now U.S. Pat. No. 5,741,812. which is a continuation inpart of U.S. patent application Ser. No. 08/645,467, filed on May 13,1996, now U.S. Pat. No. 5,650,431, which is a continuation in part ofU.S. patent application Ser. No. 08/378,414, filed on Jan. 26, 1995, nowU.S. Pat. No. 5,516,791, which is a divisional of U.S. patentapplication Ser. No. 08/174,534, which was filed on Dec. 28, 1993, nowU.S. Pat. No. 5,416,106.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to thromboxane receptor ligands includinga carboxylic acid group derivative, which do not cause blood clotting.In particular, the thromboxane receptor ligands are bicyclic carboxylicacid derivatives wherein said bicyclic rings may be hydrocarbyl oroxohydrocarbyl, e.g. 7-[carboxyalkyl or alkenyl]-6-[alkyl oralkenyl]-3-oxo-2,4-dioxobicyclo[3.2.1] octanes and derivatives thereof.In particular, hydroxyl, nitro, amino, amido, azido, oxime, thiol, etherand thiol ether derivatives of said carboxylic acid group arecontemplated. In particular,7-[6-carboxy-2-hexenyl]-6-[3-hydroxy-1-octenyl]3-oxo-2,4-dioxobicyclo-[3.2.1]octane derivatives are disclosed. These compounds are useful asthromboxane agonists and antagonists. These compounds are also useful asocular hypotensives.

2. Description of the Related Art

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupillary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical β-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Various U.S. Patents have recently issued which relate to thromboxaneligands and/or treating hemorrhaging. For example, U.S. Pat. Nos.5,128,322; 5,128,354; 5,149,540; 5,389,630; 5,415,863; 5,436,260;5,447,712; 5,482,960; 5,478,844 and 5,504,090 relate to methods oftreating hemorrhaging. U.S. Pat. Nos. 5,248,507; 5,264,220; 5,382,569;5,409,956; 5,443,848; 5,476,846; 5,480,645; 5,482,960 and 5,504,090relate to thromboxane ligands. It is thus clear that a great deal ofresearch is currently involved in thromboxane ligands, especially fortreating hemorrhaging and related conditions.

SUMMARY OF THE INVENTION

We have found that certain bicyclic carboxylic acid derivatives, whereinsaid bicyclic rings may be hydrocarbyl or oxy hydrocarbyl, e.g.7-[carboxylalkyl or alkenyl]-6-[alkyl oralkenyl]-3-oxo-2,4-dioxobicyclo[3.2.1] octane derivatives thereof, e.g.hydroxyl, nitro, amino, amido, azido, oxime, thiol, ether and thiolether derivatives of said carboxy group are potent ocular hypotensiveagents. We have further found that these compounds are thromboxaneligands and may have the unique ability, described herein, to mimic thevasoconstrictor properties of thromboxane A2 and its endoperoxideprecursors, without causing concomitant platelet aggregation, i.e. bloodclotting, and therefore said compounds provide a diverse variety ofmedical uses. Their potent vasoconstrictor properties may be safely usedin therapy as they do not cause the platelet aggregation and resultantthrombosis that would arise from using known thromboxane mimetics.

The vasoconstrictor properties would substantially reduce blood flow inblood vessels and could be used to prevent hemorrhaging associated withexternal or internal injuries without the risk of thrombosis. Thesecompounds may also be used as surgical adjuncts to reduce the bleedingfrom incisions at any anatomical location. Similarly, these compoundswould be useful in limiting the bleeding associated with toothextraction. The ability of these compounds to prevent hemorrhage,without causing platelet aggregation and resultant thrombosis, allowstheir safe application in systemic diseases where hemorrhage occurs. Forexample, bleeding from the gastro-intestinal tract associated withhemorrhoids, inflammatory bowel diseases, or gastric and peptic ulcermay be prevented. Bleeding associated with stroke may be prevented.Bleeding associated with stroke may be reduced without causingthrombosis and a potentially fatal complication. Bleeding is also afrequent complication in retinal diseases and surgeries resulting inimpaired vision. This would also be amenable to safe treatment by thevascular-selective thromboxane mimetics described herein. Excessivebleeding associated with menstruation, childbirth, and uterinedysfunction may also be safely treated.

The selective vasoconstrictor properties of these compounds may be usedto treat systemic hypotension. They may also be employed to restorenormal blood pressure in haemorragic, anaphylactic, or septic shockepisodes, without the serious risks associated with typical thromboxanemimetics which would result from their pro-aggregatory effects onplatelets.

The selective vasoconstrictor properties may also be used to providelocal anti-inflammatory effects in tissues such as the eye, skin, andnose. They may also be used to limit plasma exudation in bums andscalds.

A thromboxane-like vasoconstrictor that does not cause plateletaggregation may also be useful in optimizing blood born delivery ofdrugs and diagnostics in encapsulating vehicles. For example, deliveryof drugs or diagnostic substances encapsulated in heat-sensitive orlight-sensitive liposomes to the retina may be safely enhanced by agentsdescribed herein which selectively produce vasoconstriction.

Additionally, certain of the bicyclic carboxylic acid derivatives of thepresent invention are useful as thromboxane antagonists for treatingsystemic or pulmonary hypertension, myocardial ischemia, anginapectoris, coronary contraction, cerebrovascular contraction aftersubarachnoidal hemorrhage, cerebral hemorrhage and asthma.

Finally, the profound ocular hypotensive activity of these cycliccarbonate compounds is unexpected, given that the benchmarkthromboxane/endoperoxide mimetic U-46619 (Coleman, R. A., et.al., Br. J.Pharmacol. 73:773-778, 1981) causes ocular hypertension in primates. Thecompounds herein would, therefore, be useful for treating glaucoma andocular hypertension. They may be particularly useful as ocular surgicaladjuncts for preventing ocular hypertensive episodes and reducing localbleeding that may occur post-surgically without complications inherentin blood clotting.

The present invention relates to methods of treating ocular hypertensionand other diseases and conditions wherein thromboxane ligands are usefulfor treating which comprises administering an effective amount of abicyclic carboxylic acid derivative represented by the formula I

wherein Y is (CH₂)_(x), Z is selected from the group consisting of

O, OCH₂, O—C—O and (CR₂)_(x), x is an integer of 1 or 2, n is 0 or 1; R₂is hydrogen or an alkyl radical of from 1 to 4 carbons, e.g. methyl, orethyl; A is an alkylene or alkenylene radical having from two to sevencarbon atoms, e.g. about four to six carbon atoms, which radical may besubstituted with one or more hydroxy, oxo, alkyloxy or alkylcarboxygroups or said alkylene or alkenylene may have one or more enchained oxaor imino radicals; B is a methyl radical or a cycloalkyl radical havingfrom three to seven carbon atoms, e.g. about five to six carbon atoms,or an aryl radical, selected from the group consisting of hydrocarbylaryl and heteroaryl radicals wherein the heteroatom is selected from thegroup consisting of nitrogen, oxygen and sulfur atoms; and X is selectedfrom the group consisting of nitro, cyano, —COOR, —CH₂OR₁, —C(O)N(R₁)₂,—CH₂N(R₁)₂—CH═N—OH and —CH₂SR₁ radicals, wherein R is C₁ to C₁₀ alkyl,phenyl or benzyl and R₁ is R or hydrogen; or a pharmaceuticallyacceptable salt thereof. For example, A may be a straight chain alkyleneradical, e.g. heptylene, or alkenylene radical, e.g.3-hydroxy-1-heptylenyl, or an ethylenyloxyethylenyl radical or aminocarbonyl hydrazino methyl radical and B may be selected from the groupconsisting of methyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl,pyridyl, etc. B may also be substituted by radicals selected from thegroup consisting of halo, e.g. fluoro, chloro, iodo etc., nitro, amino,thiol, hydroxy, alkyloxy, alkylcarboxy, etc. Preferably, B is methyl,cyclohexyl or phenyl.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of the compounds of formula I,above, as ocular hypotensives or a thromboxane ligands.

Preferably, the present invention relates to the use of a7-[carboxylalkyl or alkenyl]-6-[alkyl oralkenyl]-3-oxo-2,4-dioxobicyclo[3.2.1] octane derivative, e.g. ahydroxyl, nitro, amino, amido, azido, oxime, thiol, ether or thiol etherderivative as thromboxane ligands. These preferred therapeutic agentsare represented by compounds having the formula II,

wherein A, B and X are as defined above.

For the purpose of this invention, unless further limited, the term“aliphatic” means linear and branched alkylene and alkenylene radicals,the terms “alkylene” and “alkenylene” mean divalent radicals derivedfrom alkanes and alkenes, respectively. The term “alkyl” refers to alkylgroups having from one to ten carbon atoms, the term “cycloalkyl” refersto cycloalkyl groups having from three to seven carbon atoms, the term“aryl” refers to aryl groups having from four to ten carbon atoms. Theterm “saturated or unsaturated acyclic hydrocarbon group” is used torefer to straight or branched chain, saturated or unsaturatedhydrocarbon groups having from one to about six, preferably one to aboutfour carbon atoms. Such groups include alkyl, alkenyl and alkynyl groupsof appropriate lengths, and preferably are alkyl, e.g. methyl, ethyl,propyl, butyl, pentyl, or hexyl, or an isomeric form thereof.

More preferably the method of the present invention comprisesadministering a 7-[carboxyalkyl or alkenyl]-6-[alkyl oralkenyl]-3-oxo-2,4-dioxobicyclo[3.2.1] octane derivative represented bythe formula III,

wherein either the α or ω chain may be unsaturated, i.e. the dashedbonds represent a single bond or a double bond which can be in the cisor trans configuration and R₃ is ═O, —OH or —O(CO)R₆; wherein R₆ is asaturated or unsaturated acyclic hydrocarbon group having from 1 toabout 20 carbon atoms, or —(CH₂)_(m)R₇ wherein m is 0-10, preferably0-4; and R₇ is an aliphatic ring from about 3 to about 7 carbon atoms,or an aryl or heteroaryl ring, as defined above; or a pharmaceuticallyacceptable salt thereof.

Preferably the derivative used in the above method of treatment is acompound of formula IV,

wherein hatched lines indicate the α configuration and a solid triangleis used to indicate the β configuration.

As an aromatic ring, R₇ preferably is phenyl, and the heteroaromaticrings have oxygen, nitrogen or sulfur as a heteroatom, i.e., R₇ may bethienyl, furanyl, pyridyl, etc.

In a further aspect, the present invention relates to pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof formulae (I), (II), (III) or IV wherein the symbols have the abovemeanings, or a pharmaceutically acceptable salt thereof in admixturewith a non-toxic, pharmaceutically acceptable carrier or liquid vehicle.

Preferred representatives of the compounds within the scope of thepresent invention are the compounds of formula IV wherein X are —COOR,—CH₂OH and —C(O)N(R₁)₂, wherein R and R₁ is defined above, and thepharmaceutically acceptable salts thereof. Specific compounds within thescope of this invention are as follows:

-   -   7-[6-carbomethoxy-2-cis-hexenyl-6-[3α-hydroxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]        octane    -   7-[6-carbomethoxy-2-cis-hexenyl-6-[3α-pivaloyloxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]        octane    -   7-[7-hydroxy-2-cis-heptenyl-6-[3α-hydroxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]        octane    -   7-[6-carbobenzoxy-2-cis-hexenyl-6-[3α-hydroxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.        1] octane    -   7-[6-carbobenzoxy-2-cis-hexenyl]-6-[3α-pivaloyloxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]octane    -   7-[6-carboamino-2-cis-hexenyl-6-[3α-hydroxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]octane    -   7-[6-carboisopropylamino-2-cis-hexenyl]-6-[3α-hydroxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]        octane    -   7-[6-carboxy-2-cis-hexenyl]-6-[3α-pivaloloxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo        [3.2.1] octane    -   [1R-[1α, 4α, 5β(Z), 6α(1E,        3S*)-7-[6-(3-hydroxy-1-octenyl)-2-oxabicyclo[2.2.1]hept-5-yl]-5-hepten-1-ol    -   [1S-[1α, 2β(Z), 3(1E, 3R*),        5α]]-7-[3-(3-hydroxy-1-octenyl)-6,6-dimethybicyclo[3.1.1]hept-2-yl]-5-hepten-1-ol    -   [1S-[1α, 2α(Z), 3β (1E, 3S*),        4α]]-7-[3-(3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-hepten-1-ol    -   [1S-[1α, 2α(5Z), 3α,        4α]]-7-[3-[2-(phenylamino)-carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-hepten-1-ol

A pharmaceutically acceptable salt is any salt which retains theactivity of the parent compound and does not impart any deleterious orundesirable effect on the subject to whom it is administered and in thecontext in which it is administered. Such salts are those formed withpharmaceutically acceptable cations, e.g., alkali metals, alkali earthmetals, amines, etc.

The compounds utilized in the method of the present invention can beprepared and administered in a wide variety of oral and parenteraldosage forms. Thus, the compounds of the present invention can beadministered by injection, that is, intravenously, intramuscularly,intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.Also, the compounds of the present invention can be administered byinhalation, for example, intranasally. Additionally, the compounds ofthe present invention can be administered transdermally. It will beobvious to those skilled in the art that the following dosage forms maycomprise as the active component, either a compound of formulas Ithrough IV or a corresponding pharmaceutically acceptable salt of acompound of formulas 1 through IV.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active compounds is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit: doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 100 mg preferably 0.5 mg to 100 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use, the compounds utilized in the method of thisinvention are administered at the initial dosage of about 0.01 mg toabout 10 mg/kg daily. The dosages, however, may be varied depending uponthe requirements of the patient, the severity of the condition beingtreated, and the compound being employed. Determination of the properdosage for a particular situation is within the skill of the art.Generally, treatment is initiated with smaller dosages which are lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

Pharmaceutical compositions for treating glaucoma or loweringintraocular pressure may be prepared by combining a therapeuticallyeffective amount of at least one compound according to the presentinvention, or a pharmaceutically acceptable salt thereof, as an activeingredient, with conventional ophthalmically acceptable pharmaceuticalexcipients, and by preparation of unit dosage forms suitable for topicalocular use. The therapeutically efficient amount typically is betweenabout 0.0001 and about 5% (w/v), preferably about 0.001 to about 1.0%(w/v) in liquid formulations.

For ophthalmic application, preferably solutions are prepared using aphysiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 4.5 and 8.0with an appropriate buffer system, a neutral pH being preferred but notessential. The formulations may also contain conventional,pharmaceutically acceptable preservatives, stabilizers and surfactants.

Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose cyclodextrin and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. The preferred chelating agent isedentate disodium, (sodium EDTA) although other chelating agents mayalso be used in place of or in conjunction with it.

The ingredients are usually used in the following amounts: IngredientAmount (% w/v) active ingredient about 0.001-5 preservative   0-0.10vehicle   0-40 tonicity adjustor   0-10 buffer 0.01-10 pH adjustor q.s.pH 4.5-7.5 antioxidant as needed surfactant as needed purified water asneeded to make 100%

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The ophthalmic formulations of the present invention are convenientlypackaged in forms suitable for metered application, such as incontainers equipped with a dropper, to facilitate application to theeye. Containers suitable for dropwise application are usually made ofsuitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution. One package may contain oneor more unit doses.

Especially preservative-free solutions are often formulated innon-resealable containers containing up to about ten, preferably up toabout five units doses, where a typical unit dose is from one to about 8drops, preferably one to about 3 drops. The volume of one drop usuallyis about 20-35 μl.

This invention is further illustrated by the following non-limitingexamples.

EXAMPLE 1 cyclopentane heptenoic acid,5-cis-2-(3α-t-butyldimethyl-silyloxy-1-trans-octenyl)-3,5-dihydroxy,[1α, 2β, 3α, 5α]methyl ester

PGF2α (542 mg, 1.53 mmol) was dissolved in ethylether (Et₂O) (20 mL) andcooled to O° C. A solution of CH₂N₂ in Et₂O was added dropwise to theabove suspension until a yellow color persisted. The solution was warmedto 25° C. for 0.5 h and then concentrated in vacuo to yield PGF 2αmethyl ester as an oil.

The crude ester was heated at reflux with n-butyl boronic acid (0.188 g,1.84 mmol) in CH₂Cl₂(3.1 mL) for 2 h. The volatiles were removed undervacuum to yield the crude boronate ester which was immediately dilutedwith CH₂Cl₂ (3 mL) and cooled to 0° C. 2,6-Lutidine (0.43 mL, 3.7 mmol)was added followed by t-butyldimethylsilyl trifluoromethane-sulfonate(0.67 mL, 2.9 mmol). The reaction solution was then warmed to 23° C. for16 h, concentrated, and rediluted with methanol (40 mL). After stirringfor 24 h, the methanol was removed under vacuum and the residue waspurified by FCC (2:1 hexane (hex)/ethyl acetate (EtOAc), silica gel) toyield (0.697, 92% yield) of the named product as an oil.

EXAMPLE 27-[6-carbomethoxy-2-cis-hexenyl]-6-[3α-t-butyldimethylsilyloxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]octane

149 mg (0.318 mmol) of the compound of Example 1 were dissolved in 1.6ml of CH₂Cl₂ and cooled to at −78° C. 0.154 mL (0.6 mmol) of pyridinewere then added and stirring was continued for 5 minutes. 48 mg (0.5mmol) of triphosgene dissolved in 1 mL CH₂Cl₂ was slowly added and theresulting mixture was stirred for an additional hour before beingallowed to slowly warm to room temperature. After standing overnight thereaction was quenched with saturated aqueous NH₄Cl, diluted with EtOAcand the resulting reaction mixture was worked up washing the organicportion with 1 N HCl, NaHCO₃ and brine. The organic layer was dried overanhydrous MgSO₄, filtered and concentrated in vacuo to yield 149 mg of acrude fraction including the named compound.

EXAMPLE 37-[7-hydroxy-2-cis-heptenyl]-6-[3α-t-butyldimethylsilyloxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]octane

73 mg (0.143 mmol) of the compound of Example 2 were dissolved in a 0.28mL of ethylether (Et₂O) and then 3.0 mg of lithium borohydride (LiBH₄)were added and the mixture stirred at 23° C. overnight. The reaction wasquenched using 2.0 N NaOH and the resulting reaction mixture was workedup by extraction with EtOAc and washing the organic portion with brine.The resulting organic layer was concentrated in vacuo and dried overanhydrous MgSO₄ to yield 63 mg of the named compound.

EXAMPLE 47-[7-hydroxy-2-cis-heptenyl]-6-[3α-hydroxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]octane

14 mg (0.03 mmol) of the compound of Example 3 were dissolved in TBF and0.045 mL of a 1.0 M solution of tetrabutyl ammonium fluoride (Bu₄NF)were added. After stirring under argon at room temperature for 5 hoursthe resulting reaction mixture was worked up by dilution with EtOAc andwashing with H₂O. The organic layer was dried over anhydrous MgSO₄,filtered, and concentrated in vacuo to yield 83 mg of crude product. Thecrude product was purified by elution on silica gel with a solution of60% EtOAc in hexane to yield the named compound.

EXAMPLE 4a cyclopentane heptenoic acid,5-cis-2-(3-t-butyldimethylsilyloxy-1-trans-octenyl)-3,5-dihydroxy,[1α,2β, 3α, 5α]benzyl ester

A solution of the ester of Example 1 (556 mg, 1.17 mmol) in 0.5 Naqueous lithium hydroxide (3.5 mL, 1.76 mmol) and THF (7.0 mL) wasstirred at 23° C. for 24 h and acidified with 10% citric acid. Themixture was extracted with EtOAc and the combined organics were dried(MgSO₄), filtered and concentrated in vacuo.

The crude residue was treated with O-benzyl-N,N′-diisopropylisourea(0.41 g, 1.76 mmol) and heated to 65° C. in benzene (7.0 mL) for 24 h.The reaction was cooled to room temperature and stripped of the solvent.Flash column chromatography (silica gel, 2:1 hexane/EtOAc) of theresidue gave 553 mg (85%) of the named compound.

EXAMPLE 57-[6-carbobenzoxy-2-cis-hexenyl]-6-[3α-t-butyldimethylsilyloxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]octane

330 mg (0.591 mmol) of the compound of Example 4a were treated inaccordance with the procedure of Example 2 to yield 235.7 mg (68% yield)of the named compound.

EXAMPLE 67-[6-carbobenzoxy-2-cis-hexenyl]-6-[3α-hydroxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]octane

60 mg (0.1037 mmol) of the compound of Example 5 in 1.0 mL of THF wastreated with 0.20 mL a 1.0 M solution of Bu₄NF and stirred at 23° C. for16 hours. The reaction mixture was diluted with EtOAc, and then washed,consecutively, with H₂O and brine and dried over anhydrous MgSO₄. Thedried organic phase was filtered and the filtrate concentrated undervacuum. Elution on silica gel with a 1:1 mixture of hexane and EtOAcyielded 29.7 mg (62% yield) of the named compound.

EXAMPLE 77-[6-carboxy-2-cis-hexenyl]-6-[3α-hydroxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]octane

A suspension of 25 mg (0.0531 mmol) of the compound of Example 6 and 8mg of a catalyst comprising 10% Palladium, by weight, on carbon in a 1:4mixture 1-methyl-1,4-cyclohexadiene and methanol (1.25 mL) was heated at35° C. In 20 minutes the reaction was complete and the reaction mixturewas diluted with CH₂Cl₂ and filtered. The filtrate was concentrated invacuo and eluted on silica gel with EtOAc to yield 20 mg (99% yield) ofthe named compound.

EXAMPLE 8 cyclopentane heptenoic acid,5-cis-2-(3α-hydroxy-1-trans-octenyl)-3,5-hydroxy,[1α, 2β, 3α, 5α]benzylester

1.75 g (4.93 mmol) of the prostaglandin F₂α were mixed with 1.73 g (7.40mmol) of O-benzyl-N,N′-diisopropylisourea in 25 mL of benzene and heatedto 65° C. for 4 h. After removal of the solvent, treatment byconsecutive elution on silica gel with a 1:1 mixture of hexane and EtOAcfollowed by 95:5 mixture of EtOAc and methanol gave 2.08 g (95% yield)of the named compound.

EXAMPLE 9

cyclopentane heptenoic acid,5-cis-2-(3α-pivaloyloxy-1-trans-octenyl)-3,5-dihydroxy,[1α, 2β, 3α,5α]benzyl ester

1.13 gm (2.54 mmol) of the compound of Example 8 and 0.39 g (3.81 mmol)of n-butylboronic acid in 28 mL of toluene were heated at reflux for 72hours with azeotropical removal of water. The reaction mixture wascooled to 23° C. and concentrated in vacuo. The residue was diluted withCH₂Cl₂ and allowed to react with 0.77 mL (3.81 mmol) oftrimethylacetylchloride, 1.06 mL (7.63 mmol) of triethylamine and 155 mg(1.27 mmol) of DMAP (4-dimethylaminopyridine) at 23° C. for 48 hours.The resulting reaction mixture was concentrated, in vacuo, dissolved inmethanol and stirred overnight. The methanol was removed in vacuo andthe residue was purified by elution on silica gel with a 2:1 mixture ofhexane and EtOAc to afford 0.87 gm (65% yield) of the named compound wasobtained.

EXAMPLE 10 cyclopentane heptenoic acid,5-cis-2-(3α-pivaloyloxy-1-trans-octenyl)-3-hydroxy, 5-imidazolyloxy[1α,2β, 3α, 5α]benzyl ester

211 mg (0.399 mmol) of the compound of Example 9 and 77.7 mg (0.479mmol) of 1,1-carbonyldiimidazole were dissolved in 1.0 mL of CH₂Cl₂ andstirred for 24 hours at 23° C. to yield the named compound.

EXAMPLE 117-[6-carbobenzoxy-2-cis-hexenyl]-6-[3α-pivaloyloxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]octane

0.133 mmol of the compound of Example 10 and 0.14 mL (1.33 mmol) oft-butylamine dissolved in CH₂Cl₂ were heated to 45° C. for 48 hours. Thereaction mixture was cooled to room temperature, concentrated in vacuoand eluted on silica gel with a 3:1 mixture of hexane and EtOAc to yield31 mg (42% yield) of the named compound.

EXAMPLE 127-[6-carboxy-2-cis-hexenyl]-6-[3α-pivaloyloxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]octane

The compound of Example 11 was treated according to the procedure ofExample 7 to yield the named compound.

EXAMPLE 13 cyclopentane heptenamide,5-cis-2-[3α-t-butyldimethylsilyloxy-1-trans-octenyl)-3,5 dihydroxy, [1α,2β, 3α, 5α]

460 mg (0.954 mmol) of the compound of Example 1 was reacted with anexcess of NH₃ in 6.0 mL of methanol to yield a solution including thenamed compound. The excess solvent and unreacted NH₃ were evaporated andthe residue was purified by elution on silica gel, consecutively, with100% EtOAc followed by a 9:1 mixture of CH₂Cl₂ and methanol to yield 395mg (89% yield) of the named compound.

EXAMPLE 147-[6-carboamino-2-cis-hexenyl]-6-[3α-t-butyldimethylsilyloxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]octane

256 mg (0.548 mmol) of the compound of Example 13, 5 mg (0.040 mmol) of4-dimethylamino pyridine (DMAP) and 98 mg. (0.602 mmol) of 1,1carbonyldiimidazole were reacted in 1.5 ml of CH₂Cl₂, for 24 hours at23° C. The resulting reaction solution was concentrated in vacuo and theresidue purified by elution with 100% EtOAc. The resulting reactionproduct was stirred with 71 uL DBU (0.474 mmol) in 1.0 mL of benzene for24 hours at 23° C. After concentration in vacuo and elution on silicagel with a 2:1 mixture of EtOAc and hexane, 25 mg (10% yield) of thenamed compound were obtained.

EXAMPLE 157-[6-carboamino-2-cis-hexenyl]-6-[3α-hydroxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]octane

The compound of Example 14 was converted into the named compound at 95%yield by the procedure of Example 6.

EXAMPLE 167-[6-carboxy-2-cis-hexenyl]-6-[3α-t-butyldimethylsilyloxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]octane

156 mg (0.267 mmol) of the compound of Example 5 were treated inaccordance with the procedure as Example 7 to yield the correspondingcarboxylic acid (99%) yield).

EXAMPLE 177-[6-carboisopropylamino-2-cis-hexenyl]-6-[3α-hydroxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]octane

75 mg (0.151 mmol) of the compound of Example 16 in CH₂Cl₂ were reactedwith 1.5 mL of SOCl₂ at 0° C. for 1 h. 69 mg (1.17 mmol) ofisopropylamine were added and the resultant solution was warmed to 23°C. for 16 h to yield a reaction mixture which upon removal of the excesssolvent and purification by elution on silica gel with a 1:1 mixture ofhexane and EtOAc gave 4.8 mg (8% yield) of the named compound.

EXAMPLE 18A cyclopentane heptenoic acid,5-cis-2-(3α-pivaloyloxy-1-trans-octenyl)-3,5-dihydroxy,[1α, 2β, 3α,5α]methyl ester

PGF₂α methyl ester (prepared as described in Example 1) was treatedaccording to the procedure of Example 9 to yield the named compound.

EXAMPLE 18B cyclopentane heptenoic acid,5-cis-2-(3α-pivaloyloxy-1-trans-octenyl)-3-hydroxy, 5-imidazolyoxy, [1α,2β, 3α, 5α]methyl ester

A solution of the compound of Example 18A (75 mg 0.166 mmol) in THF (1.0mL) was heated to 50° C. and triphosgene (16.4 mg, 0.0553 mmol) wasadded. After 2 h imidazole (22.6 mg, 0.332 mmol) was added and a whiteprecipitate formed immediately. The reaction was stirred an additional16 h, allowed to cool to room temperature, and concentrated in vacuo.Purification of the residue by FCC (1:1 hex/EtoAc, silica gel) affordedthe 45.3 mg of the named compound, i.e 50% yield.

EXAMPLE 18C7-[6-carbomethoxy-2-cis-hexenyl]-6-[3α-pivaloyloxy-1-trans-octenyl]-3-oxo-2,4-dioxobicyclo[3.2.1]octane

A solution of the compound of Example 18B (17.4 mg, 0.032 mmol) inbenzene (0.75 mL) was treated with 1,8-diazabicyclo [5.4.0]undec-7-ene(DBU) (24 μL, 0.159 mmol) at 23° C. After 12 h the reaction solution wasconcentrated in vacuo and the residue was purified by FCC (1:1hex/EtoAc, silica gel) to give 12.9 mg (85% yield) of the namedcompound.

EXAMPLE 19 [1R-[1α, 4α, 5β(Z), 6α(1E,3S*)-7-[6-(3-hydroxy-1-octenyl)-2-oxabicyclo[2.2.1]hept-5-yl]-5-hepten-1-ol

A solution of U-46619 (10 mg, 0.0285 mmnol) in methyl acetate (1.0 mL)was treated with diazomethane in ether (˜1/2 mL) at O°. The resultantyellow solution was allowed to warm to room temperature, concentrated invacuo to give 10.3 mg (99%) of the methyl ester of U-46619.

Lithium borohydride (28 ul of a 2.0 M solution in tetrahydrofuran THF,0.0565 mmol) was added to a solution of the methyl ester of U-46619(10.3 mg, 0.282 mmol) in diethylether (Et₂O)(1.5 mL) at 23° C. After 24h TLC indicated only a lower Rf product. The reaction was quenched withIN NaOH, stirred 1 h and extracted with CH₂Cl₂. The organic portion wasdried over Na₂SO₄, filtered and concentrated in vacuo. Flash columnchromatography (silica gel, 1:1 hexane/EtOAc) gave 9.0 mg (95%) ofalcohol.

EXAMPLE 20 [1S-[1α, 2β(Z), 3(1E, 3R*),5α]]-7-[3-(3-hydroxy-1-octenyl)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]-5-hepten-1-ol

The title compound was prepared in accordance with the proceduresdescribed above in Example 19 with Pinane thromboxane A₂ replacingU-46619.

EXAMPLE 21 [1S-[1α, 2α(Z), 3β(1E, 3S*),4α]]-7-[3-(3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-hepten-1-ol

The title compound was prepared in accordance with the proceduresdescribed above in Example 19 with I-BOP replacing U-46619.

EXAMPLE 22 [1S-[1α, 2α(5Z), 3α,4α]]-7-[3-[2(phenylamino)carbonyl]-hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-hepten-1-ol

The title compound was prepared in accordance with the proceduresdescribed above in Example 19 with SQ-29,548 replacing U-46619.

Prostanoid Receptor Activity

Activity at different prostanoid receptors was measured in vitro inisolated smooth muscle preparations. FP-activity was measured ascontraction of the isolated feline iris sphincter. EP₁-activity wasmeasured as contraction of the longitudinal smooth muscle of theisolated guinea pig ileum. EP₃-activity was measured as inhibition ofthe twitch response induced by electrical field stimulation in theisolated guinea pig was deferens and as contraction of the longitudinalsmooth muscle of the isolated chick ileum. TP-vasoconstrictor activitywas measured as contraction of rings of the isolated rat thoracic aorta.Effects on platelets from healthy human donors were measured byincubating platelet-rich plasma with the compounds described herein.Inhibition of aggregation was determined by the ability of the compoundsdescribed herein to inhibit platelet aggregation in platelet-rich plasmainduced by 20 μM ADP. The activity profile of various compounds isreported in Tables 1 and 7.

In addition, inhibition by the thromboxane A2-receptor antagonistSQ29,548 ([1S-[1α, 2α(5Z), 3α,4α]]-7-[3-[[2-[phenylamino)carbonyl]-hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoicacid) of vasoconstrictor activity was investigated. For that purpose,activity of the compound of Example 4, the compound of Example 7, andU-46619 (9,11-dideoxy-9α,11α-methanoepoxy prostaglandin F_(2α)), apotent and stable thromboxane A₂ analog, was measured in rings of theisolated rat thoracic aorta, first in the absence and then in thepresence of SQ29,548 (1 uM). The results are reported in Table 2.

EXAMPLE 23 Pharmacological Selectivity for a Tp-receptor Subtype Presenton Vascular Smooth Muscle

Examination of Tables 1 and 7 reveals an unexpected and unique trend inbiological activity associated with certain examples of formula IV.Typically, thromboxane (TP-) receptor agonists indiscriminately causeboth platelet aggregation and smooth muscle contraction. It has,therefore, been concluded that there is no convincing evidence thatsubtypes of the TP-receptor exist (Jones, R. L., Wilson, N. H.,Armstrong, R. A., Tymkewycz, P. M. Colloque INSERM 152:335-344, 1987).Examples 4, 15 and 16 and 19 through 21 exhibit pronounced activity incontracting vascular smooth muscle but have no or minimal ability tocause platelet aggregation.

Further evidence is provided below to demonstrate that the ability ofexamples 4, 15 and 16 and 19 through 21 to cause contraction of vascularsmooth without causing platelet aggregation involves selectivestimulation of a subtype of TP-receptor present on vascular smoothmuscle.

-   1. A TP-receptor antagonist blocks the effect of agonists which are    selective for the vascular TP-receptor (Example 4) and non-selective    with respect to vascular and platelet TP-receptors (Example 7,    U-46619), see Table 2. This shows that Example 4 and its congeners,    which show selectivity for contracting vascular smooth muscle,    produce their effect by interacting with a subtype of TP-receptor as    opposed to some other type of eicosanoid receptor.-   2. The compound Example 4 neither causes platelet aggregation nor    inhibits the ability of U-46619. or Example 7 to cause platelet    aggregation, see Table 3. Moreover, Example 4 did not inhibit ADP or    arachidonic acid induced platelet aggregation (Table 4) and,    therefore, its activity cannot be ascribed to a mechanism which    opposes the aggregatory response, e.g., behaving as a prostacyclin    or prostaglandin D2 mimetic, inhibition of cyclooxygenase.

Thus, it appears that certain examples of formula IV selectivelyconstrict smooth muscle by stimulating a TP-receptor subtype whichexists on smooth muscle but not on platelets. Such antagonists may beuseful in treating systemic and local vasoconstriction and otherindications without concommitant inhibition of normal platelet functionand blood clotting.

EXAMPLE 24 Effects on Intraocular Pressure

The effects of four examples of formula IV and the thromboxane mimeticU-46619 on intraocular pressure are provided in the following tables.The compounds were prepared at the said concentrations in a vehiclecomprising 0.1% polysorbate 80 and 10 mM TRIS base. Dogs and monkeyswere treated by administering 25 ul to the ocular surface, thecontralateral eye received vehicle as a control. Intraocular pressurewas measured by applanation pneumatonometry. Experiments were performedwith dogs and monkeys. Dog intraocular pressure was measured immediatelybefore drug administration and at 2, 4 and 6 hour thereafter. Additionalstudies in monkeys were performed over a 5 day period and drug wasadministered at times 0, 6, 24, 30, 48, 54, 72, 78, and 96 hours. Monkeyintraocular pressure was recorded just before drug administration oneach day and at the 2 and 4 hour time intervals between dosing.

The examples of formula IV examined showed a pronounced ocularhypotensive effect in both dogs and monkeys (Tables 5 and 6). Incontrast, the thromboxane/endoperoxide mimetic U-46619 produced anincrease in intraocular pressure. Thus, the cyclic carbonate derivativesdescribed herein caused a profound decrease in intraocular pressurewhich was unexpected given the absence of ocular hypotensive activityassociated with U-46619. Since the in vitro pharmacological effects ofthe cyclic carbonate analogs (a) cannot be attributed to stimulation ofother known prostanoid receptors and (b) are susceptible to athromboxane antagonist, it is concluded that the ocular hypotensiveactivity of these compounds is related to selective stimulation of athromboxane receptor subtype.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent from one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same results. In particular, other thromboxane ligands comprising acarboxylic acid derivative may be prepared from the parent carboxylicacid to obtain thromboxane receptor agonists which are useful intreating hemorrhage by constricting the cardiovascular network withoutthe side effect of causing blood clotting or thromboxane antagonists,which are useful in treating hypertension without the side effect ofcausing blood clotting. Thus, in general TRL—COOH, wherein TRLrepresents a thromboxane receptor ligand residue may be converted bymethods known in the art to TRL-W, wherein W is C(O)(NR₁)₂, CH₂OR₁, CH₂N(R₁)₂ or COOR wherein R and R₁ are as defined above. Certain compoundswhich are useful as TRL—COOH are described in CRC Handbook ofEicosanoids: Prostaglandins and Related Lipids Vol. I: Part B, at pages35-40 and Developments in the Characterization of ProstaglandinEndoperoxide/fhromboxane Receptors, Colloque INSERM, Vol. 152, 1987, pp335 to 344 which references also refer in many instances to methods forpreparing such compounds. These compounds are described in Tables 8 and9 below. In addition, the compounds represented by formulae: I and IImay have the following orientation:

Thus, however detailed the foregoing may appear in text, it should notbe construed as limiting the overall scope hereof; rather, the ambit ofthe present invention is to be governed only by the lawful constructionof the appended claims. TABLE 1 EFFECT OF EXAMPLES OF FORMULA IV ATDIFFERENT PROSTANOID RECEPTOR SUBTYPES COMPOUND EC₅₀ (nM) VALUES ATPROSTANOID RECEPTOR SUBTYPES EP₁ EP₃(c) EP₃(d) TP_(γasc) EP (Guinea(Guinca Pig (Chick (Rat Platelets (Human) Inhibition (Cat Iris) Pigleum) vas deferens) Ileum) Aorta) Aggregation of Aggregation Example 7433 1,240 282 245 0.23   24 N/A Example 4 485 N/A 2,930 >10⁴ 1.0   >10⁴N/A Example 17 3,020 324 N/A N/A Example 15 387 58 3,110 N/AEC₅₀ (nM) = nM concentration required to produce a 50% of maximalresponse

TABLE 2 EFFECT OF THE THROMBOXANE (TP)-RECEPTOR ANTAGONIST SQ 29548 ONCONTRACTION OF THE RAT AORTA PRODUCED BY EXAMPLES OF FORMULA IV EC₅₀ atTP_(γasc)-RECEPTOR COMPOUND −SO29,548 +SO29,548 Example 7 2 325 Example4 0.9 454 U-46619 13 8,080

TABLE 4 Effect of Example 4 on Agonist-Induced Platelet AggregationInduced by Arachidonic Acid and ADP Agonist Response: 10-7 M 10-6 M % ofExample 4 Example 4 Agonist: max response pretreatment pretreatment 800μM 101.6 + 1.3 98.0 + 1.8 98.8 + 1.1 Arachidonic Acid  20 μM ADP   100 +0 (standard) 99.9 + 1.4 97.6 + 1.8  2 μM ADP  73.8 + 11.17 68.3 + 12.973.1 + 14.3

TABLE 3 Effect of Example 4 on Example 7 and U46619-induced PlateletAggregation Agonist Response: 10-7 M 10-6 M % of Example 4 Example 4Agonist: max response pretreatment pretreatment 10-9 Example 7    0 10-8Example 7  −7.9 + 1.3  −8.4 + 0.9  −8.0 + 2.9 3.3 × 10-8 Example 7 −8.8 + 1.3  −9.0 + 1.6  −7.3 + 0.7 10-7 Example 7   100.5 + 2.2  97.8 + 1.7   99.5 + 1.7 10-6 Example 7   103.0 + 1.9   95.3 + 0.9  96.5 + 0.9 10-8 U46619    0 10-7 U46619  −7.0 + 1.1  −5.5 + 1.1 −5.6 + 0.9 3.3 × 10-7 U46619    97.7 + 1.6   93.8 + 2.3   94.2 + 2.810-6 U46619   100.0 + 1.9   94.6 + 2.6   96.0 + 0.8

TABLE 5 The effect of compounds of Formula IV and U-46619(9,11-dideoxy-9α,11α, methanoepoxy prostaglandin F_(2α)) on dogintraocular pressure. INTRAOCULAR PRESSURE CHANGES AT PREDETERMINEDTIMES (hr) AFTER DOSING FORMULA III (Dose %) 2 HR 4 HR 6 HR U-46619 0.1% +0.86 +1.75 +2.7 Example 7 0.01% −9.7** −11.4** −11.25** Example 4 0.1% −6.7** −7.7** −8.5** Example 11  0.1% −6.9** −7.7** −9.4** Example12  0.1% −3.8** −4.7** −6.9****p < 0.01, Student's paired t test.

TABLE 6 The effect of compounds of Formula IV and U-46619(9,11-dideoxy - 9α, 11α, methanoepoxy prostaglandin F_(2α)) on monkeyintraocular pressure. INTRAOCULAR PRESSURE CHANGES AT PREDETERMINEDFormula TIMES (HR) AFTER DOSING III Dose (%) 0 2 4 6 24 26 28 30 48 50U-46619 0 **2.0 0.3 *1.0 Example 7 0.01% 0 −0.4 0 0 −1.0 *3.2 **−4.6−3.2 −1.8 −3.8 INTRAOCULAR PRESSURE CHANGES AT PREDETERMINED FormulaTIMES (HR) AFTER DOSING III 52 54 72 74 76 78 96 98 100 U-46619 Example7 *−4.0 *−4.2 *4.2 −2.0 −3.2 −4.0 −2.0 −2.2 *−3.2*p < 0.05 Students' paired t test**p < 0.01

TABLE 7 EC₅₀ (nM) Plalelets (Rat Aorta) aggreg inhib

10 320 nM NA

26 NA NA

203 950

929 NA

2.0 214 nM NA

0.4 NA NA

K_(B) = 1.6 K_(B) = 30.6 nM

K_(B) = 18.2 K_(B) = 4500 nM

TABLE 8 TXA ANALOGS Mol. formula No. Systematic name Structure (mol.wt.) Synthesis Biological actions 1 9α,11α-Carba-15α-hy- droxythromba-(Z)5,(E)13-dienoic acid

C₂₁H₃₄O₄(350) From 1-(3-hydroxy-trans-1-pro- penyl)cyclobutan-3-one¹ 29α,11α-Epoxy-15α-hy- droxy-11α-carbath- romba-((Z)5,(E)13- dienoic acid

C₂₁H₃₄O₄(350) Via a Demjanov-Tiffenau² ring expansion of PGA₂ methylester 15-r-butyldimethylsilyl ether to a 6-membered enone which wasconjugated, epoxidised, reduced to a 9,11-diol and cyclized to theoxetane³ # Inhibitor of PGH₂-induced ag- gregation of HPRP³ 3 Methyl9α,11α-epithia- 15α-hydroxy- thromba(Z)5,(E)13- dienoate

C₂₁H₃₄O₄S(382) From TXB₂ methyl ester 11- methyl ether 15-benzoate byin- version of 11α-OH, mesylation, formation of 11-methoxycarbon-ylethylthio derivative, and cyclization⁴ Contracted rat aortic strip;CD_(m) =10⁻³ M⁴ 4 9α,11α-Carba-15α-hy- droxy-11α-carbath-romba-(Z)5,(E)13- dienoic acid (carbo- cyclic TXA₂)

C₂₂H₃₆O₃(348) From 2-formylbicyclo [3.1.1]hept-2-ene⁵; for othersyntheses see Refs. 6, 7 Potent TXA₃-like agonist on the vasculature butprofound TXA antagonist on the aggregation # of platelets; profoundconstric- tion of isolated prefused corn- nary arteries (e.g., cat; 10⁴×TXB₁) Exacerbated ischemic damage in the heart (without induction ofplatelet aggregation) during coronary insufficiency (anes- thetized cat.i.v.) 7 2,3,4-Trinor-1,5-inter-m- phenylene-9α,11α-di-methylcarba-15α-hy- droxy-11α- carbathromba- (E)5,(E)13-dienoic acid

C₂₁H₃₄O₃(410) From(−)myrtenol¹¹ Inhibited vascoconstriction of isolatedperfused cat coronary artery induced by carbocyclic # TXA₂ by 72% at 1μM¹¹ 8 9α,11α-Dimethylcarba- 15α-hydroxy-16-(4- fluorophenoxy)-ω-tetra-nor-11α-carbathromba- (Z)5,(E)13-dienoic acid

C₂₆H₂₉FO₄(430) From nopol¹¹ Precipitated irreversible aggre- gation ofHPRP at 0.31 μM¹²; partial agaonist in the rabbit aorta, dog saphenousvein, and guinea pig trachea assays¹⁹ 9 9α,11α-Dimethylcarba-13-aza-13H-15α- and 15β-hydroxy-20-n-pro- pyl-11α-carbothroma-(Z)5-enoic acid

C₂₆H₄₁NO₃(421) TXA₂ antagonist on platelets and vasculature; inhibitedag- gregation of HPRP induced by STA₂ (compound 10), 9,11- methanoepoxyPGH₂, AA, col- lagen, and ADP (second phase bus not first) with IC₅₀values of 0.11-0.38 μM; also inhib- ited TXA₂ induced aggregation ofHPRP but had no effect on cyclooxygenase, TX synthe- tase, or PGE₂synthetase I.V. infusion in guinea pigs or cats (1-10 μg/kg/min) causedex vivo inhibition of AA or STA₂-induced aggregation Inhibitedvasoconstrictior re- sponse in vitro (rat aorta) and in vivo (guineapig. I.V.) in- duced by stable endoperoxide and TXA₂ analogs¹¹ 109α,11α-Epithia-15α-hy- droxy-11α-carbath- romba-(Z)5,(E)13- dienoicacid(STA₂)

C₂₁H₃₄O₂S(366) From trans-1-formyl-2-methoxy- carbonylcyclohex-4-ene¹³;also from PGA₂ methyl ester 15- acetate¹⁴ Potent, full TXA₂ agonist onplatelets and vasculature Caused rapid irreversible aggre- # gation ofHPRP; IC₅₀ = 0.6 μM Constricted isolated rat aorta. CD₅₀ = 0.4 nM, andwas a vasoconstrictor in vivo (i.v., guinea pig)²¹ 11 Methyl9α,11α-carba- 15α-hydroxy-11α- thiathromba-(Z)5,(E)13- dienoate

C₂₁H₂₆O₃S(380) From 3-vinylcyclobutanone¹⁵ Contracted isolated rataorta; CD₅₀ = 5 × 20⁻² g/ml; no effect on HPRP¹⁵ 12 9α,11α-Carba-15α-hy-droxy-11α-imino- thromba-(Z)5,(E)13- dienoic acid

C₂₁H₃₃NO₃(349) From cis-3-formylcyclobutanol¹¹ Contracted isolated rataorta; CD₅₀ = 3 × 10⁻² g/ml; no effect on HPRP¹⁷ 139α,11α-Epithia-15α-hy- droxy-11α-thiathromba- (Z)5,(E)13-dienoic acid

C₂₀H₃₃O₃S₂(384) From 4,4-dimethoxy-2-(6-chloro-2-hexyn-1-yl)-acetoacetate¹⁶ Contracted isolated rat aorta, CD₅₀ = 7 ×10⁻¹⁰ M; irrever- sibll aggregation of HPRP; IC₅₀ = 4.3 × 10⁻⁶ M¹⁶ 149α,11α-Methanoepoxy- 15α- and 15β-hydroxy- thromba (Z)5,(E)13- dienoicacid

C₂₁H₃₄O₃(366) From the product of methylena- tion oftrans-cis-cis-N,N-di- methyl-2-benzyloxy-6-methoxy-tetrahydropyran-4-one-3-aceta- mide which was obtained from the Coreylactone^(22,23) # Weak TXA₂ agonist; contraction of rabbit aorticstrips; 0.04 ×TXA₁; aggregation of rabbit PRP; 0.001 × TXA₁; did notantagonize aggregatory effect of TX₂ nor was TXA₁ syn- thetaseinhibited¹² 15 9α,11α-Methanoepoxy- 10-oxa-11α-carba-15α- and15β-hydroxy- thromba-5-cis-13-trans- dienoic acid

C₂₁H₃₄O₃(366) From trans-cis-cis-N,N-dimethyl-2,4-bis-hydroxymethyl-6-meth- oxytetrahydropyran-3- acetamide¹¹Contraction of rat aortic strips; 0.02 × TXA₁; did not aggre- # gaterabbit PRP, antagonize the aggregatory effect of TXA₁, or inhibit TXA₂synthetase¹² 16 9α,11α-Epoxy-10α- homo-15α- and 15β-hy-droxy-11α-carbath- romba-(Z)5,(E)13- dienoic acid

C₂₂H₃₄O₄(364) From [4 + 3] adduct of furan and tetrabromoacetone¹⁰ Noeffect on blood platelets; weak vasoconstrictor activity¹⁸ 17

C₂₁H₃₄O₃(378) From 1-dimethoxymethyl-2- styryl-8-oxabicyclo[3.2.1]oct-6-en-3-ol¹⁴ Mixture of C-15 epimers has strong TXA₂-like activity¹⁴

TABLE 9 a

b

c

d

e

Structures of (a) the natural compounds PGH₂ and TXA₂.(b) stable thromboxane kinetics with natural side chains,(c) potent 16-p-fluorophenoxy prostanoics(d) specific thromboxane receptor antagonists and(e) thromboxane receptor antagonists with prostacyclin-like activity.

1. A method for preparing a thromboxane agonist or antagonist havingreduced ability to cause platelet aggregation, i.e. blood clotting,which comprises converting a thromboxane ligand having the formulaTRL—COOH, wherein TRL represents a thromboxane receptor ligand residueto TRL-W wherein W is selected from the group consisting of C(O)(NR₁)₂,CH₂N(R₁)₂ or COOR wherein R is C₁ to C₁₀ alkyl, phenyl or benzyl and R₁is R or hydrogen.
 2. The method of claim 1 wherein TRL-W is a compoundformula I,

wherein Y is (CH₂)_(x); Z is selected from the group consisting of

O, OCH₂, and (CR₂)_(x), x is an integer of 1 or 2; n is 0 or 1; R₂ ishydrogen or an alkyl radical of from 1 to 4 carbons, A is an alkylene oralkenylene radical having from two to seven carbon atoms, which radicalmay be substituted with one or more hydroxy, oxo, alkyloxy oralkylcarboxy groups or said alkylene or alkenylene may have one or moreenchained oxa or imino radicals; B is a methyl radical or a cycloalkylradical having from three to seven carbon atoms, or an aryl radical,selected from the group consisting of hydrocarbyl aryl and heteroarylradicals wherein the heteroatom is selected from the group consisting ofnitrogen, oxygen and sulfur atoms, or substituted derivatives of saidmethyl, cycloalkyl or aryl radicals wherein said substituent is selectedfrom the group consisting of halo, nitro, amino, thiol, hydroxy,alkyloxy and alkylcarboxy; and X is selected from the group consistingof nitro, cyano, —COOR, —C(O)N(R₁)₂, and —CH₂N(R₁)₂ radicals, wherein Ris a C₁ to C₁₀ alkyl, phenyl or benzyl, and R₁ is R or hydrogen; or apharmaceutically acceptable salt thereof.
 3. The method of claim 2wherein said compound is a compound of formula II,


4. The method of claim 3 wherein said compound is a compound of formulaIII,

wherein either the α or ω chain may be unsaturated, i.e. the dashedbonds represent a single bond or a double bond which can be in the cisor trans configuration and R₃ is ═O, —OH or —O(CO)R₆; wherein R₆ is asaturated or unsaturated acyclic hydrocarbon group having from 1 toabout 20 carbon atoms, or —(CH₂)_(m)R₇ wherein m is 0-10, and R₇ is analiphatic ring having from about 3 to about 7 carbon atoms, or an arylradical selected from the group consisting of hydrocarbyl aryl andheteroaryl radicals wherein the heteroatom is selected from the groupconsisting of nitrogen, oxygen and sulfur atoms; or a pharmaceuticallyacceptable salt thereof.
 5. The method of claim 4 wherein said compoundis a compound of formula IV,

wherein the hatched line indicates the α configuration and the solidtriangle indicates β configuration.
 6. The method of claim 5 wherein Xis selected from the group consisting of —COOR, —CH₂N(R₁)₂ and—C(O)N(R₁)₂.